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Reducing bacterial resistance with IMPACT – Interhospital Multi-disciplinary Programme on Antimicrobial
This guideline is available for download at:
HKU Centre of Infection
http://www.hku.hk/hkucoi/impact.pdf
DH Centre for Health Protection
IMPACT Third Edition (Version 3.0)
Editors: PL Ho and SSY Wong
Third Edition 2005
Second edition: 2001 (ver 2.0), 2002 (ver 2.1), 2003 (ver 2.2)
First edition: 1999
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IMPACT Third Edition (Version 3.0)
IMPACT Working Group

Table 1. Top ten isolates from clinical specimens in 2004 (data from a
regional hospital in Hong Kong). 14
Table 2. Intrinsic and associated resistance to antimicrobial agents
among five nosocomial pathogens. 15
Table 3. Methods to implement antimicrobial control. 28
Table 4. Potential barriers to reaching the strategic goals . 29
Table 5. Summary of published data on antimicrobial strategies as an
intervention to reduce ESBL resistance. 33
Table 6. Strategies for optimization of antimicrobial therapy. 36
Table 7. Dosage table for vancomycin. 41
Table 8. Calculation of vancomycin dose for morbidly obese patient. 42
Table 9. Comparison of linezolid and quinupristin/dalfopristin. 44
Table 10. Hartford Hospital once-daily aminoglycoside normogram for
gentamicin and tobramycin . 53
Table 11. General patterns of antifungal susceptibility . 54
Table 12. Comparison of susceptibility of selected fungi to the azoles 55
Table 13. Mechanisms of antifungal action. 56
Table 14. Comparison of selected pharmacokinetic parameters for the
azoles and caspofungin . 57
Table 15. A suggested scheme for systemic antifungal agents . 58
Table 16. Criteria for severity assessment of acute pancreatitis . 72
Table 17. Prophylactic use of antibiotic in acute pancreatitis . 73
Table 18. Comparative activities of commonly used beta-lactams
against Streptococcus pneumoniae with different levels of
penicillin susceptibility. 80
IMPACT Third Edition (Version 3.0)
Foreword
Antibiotics are one of the essential armaments for management of infections.
Antimicrobial resistance results in increased morbidity, mortality, and costs of health care. It is becoming a global problem. Prevention of the emergence of
resistance and the spread of resistant microorganisms will reduce these adverse effects and their attendant costs. Promoting appropriate use of antibiotic has shown to be an effective means to control antimicrobial resistance.
In Hong Kong, our long-term battle against antibiotic resistance continues and antimicrobial guideline is an essential tool to promote rational use of
antimicrobial agents with better application of existing knowledge and adherence to good practice.
The IMPACT was developed in 1999 as a first step towards better control of the growing problem of antimicrobial resistance in Hong Kong. Developed with a multidisciplinary approach with inputs from different specialties and institutions, the IMPACT took into account the local data on prevalence of different pathogens and antimicrobial resistance patterns.
Now into its third edition, the IMPACT has incorporated constructive comments
from clinicians and other colleagues as part of an on-going effort to keep abreast of new antibiotics, changing resistance patterns and literature. This specifically developed guideline for practitioners in Hong Kong provides evidence-based principles focused on situations in which antimicrobial therapy could be curtailed without compromising patient care.
The third edition of the IMPACT is a timely update to coincide with the launching of the Antibiotic Stewardship Programme by the Hospital Authority which includes optimal selection, dose and duration of treatment, as well as control of antibiotic use. The IMPACT constitutes an essential element along with other key
elements of education, user-feedback, regular updates, clinical audits and process evaluation in this comprehensive Programme. I thank the many individuals and organizations who have contributed to the compilation of IMPACT and look forward to your continued support and
partnership in our Antibiotic Stewardship Programme.
Dr Cheung Wai-lun Director Professional Services and Operations Hospital Authority
IMPACT Third Edition (Version 3.0)
Preface

The "IMPACT" programme is a collaborative effort by recognized authorities in the areas of clinical microbiology and infection, infectious diseases, public health medicine, hospital epidemiology, intensive care medicine, respirology, surgery, orthopaedics and traumatology, and clinical pharmacology. The IMPACT working group recognizes the challenges from drug-resistant organisms and believes
that the adverse impact of antimicrobial resistance could be reduced through a better and more judicial use of the existing agents. The document is intended to be of interest and value to colleagues who practise in institutional settings and prescribe or evaluate antimicrobial agents.
This new edition updates and revises all the information in the previous edition. The document is now organized into eight parts. Part 1 and II covers the background information. Part III provides
guidelines on the use of six classes of antibiotics. They are discussed separately because they represent new agents (linezolid, quinupristin-dalfopristin), agents in which usage has a strong link to development of multidrug-resistant organisms (glycopeptides, ceftazidime, and carbapenems) or that the dosing and monitoring are complicated (aminoglycosides). Several new sections have been added: antimicrobial stewardship programme, severe acute pancreatitis, antifungal agents, and antibiotic dosing for CAPD peritonitis. The font size and the print-out size have been increased to enhance readability.
A full list of tables and a quick reference are added to facilitate the use of this book. The editors are grateful to the contributions by our experts in the working group. The secretaries are skillful and meticulous in their attention to the compilation of the document. On behalf of the working group, we thank the Infection Control Branch of the Centre for Health Protection for providing administrative support, the Chief Pharmacist Office in the Hospital Authority for the generous support in printing the hard copies and all colleagues who have provided us with their
valuable opinions in the preparation of this document. PL Ho SSY Wong November 2005
IMPACT Third Edition (Version 3.0)
Part I: Antibiotic resistance – local scenario
Part I: Antibiotic resistance- local scenario
IMPACT Third Edition (Version 3.0)
Part I: Antibiotic resistance – local scenario
Background: the problem of antimicrobial resistance in Hong Kong
1. The emergence of resistance has threatened the successful
treatment of patient with infections (1-5).
Antimicrobial resistance increases drug costs, length of stay and adversely affects patient's outcome (6).
3. Resistance to all classes of antibiotics has developed to various
extents among the common and important nosocomial pathogens (Tables 1 and 2).
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Table 1. Top ten isolates from clinical specimens in 2004 (data from a regional hospital in Hong Kong). Blood Respiratory specimens Urine Organism Organism Organism P. aeruginosa S. aureus Enterococci speciesstaphylococci K. pneumoniae H. influenzae Klebsiella speciesBacillus species KlebsiellaCandida speciesS. aureus S. pneumoniae Proteus speciesEnterococcus speciesA. baumannii P. aeruginosa A. baumannii M. catarrhalis Coagulase negative staphylococci P. aeruginosa S. aureus B. fragilis groupEnterobacter S. agalactiae
(Lancefield gp B)P. mirabilis S. maltophilia M. marganii
(Percentage omitted if number of isolates is less than 30)
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Table 2. Intrinsic and associated resistance to antimicrobial agents among five nosocomial pathogens. INTRINSIC ASSOCIATED BACTERIA RESISTANCE RESISTANCE
All beta-lactams, beta-
Common: erythromycin,
lactam/beta-lactamase
inhibitor combinations
aminoglycosides, cotrimoxazole, fluoroquinolones
All cephalosporins,
Common: ampicillin,
imipenem, meropenem,
vancomycin, high level
All cephalosporins
including fourth
fluoroquinolones,
(CTX-M, SHV-, TEM-
cephalosporin (7), all
penicillins, aztreonam
Derepressed AmpC-type First, second and third
mutant among E.
fluoroquinolones,
cloacae, C. freundii, S.
cephalosporins, most
marcescens
lactamase inhibitor combinations, cefoxitin
A. baumannii
Ampicillin, first and
Third generation
second generation
fluoroquinolones, aminoglycosides, (±
imipenem, meropenem) (8)
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Methicillin-resistant Staphylococcus aureus
On the basis of the patient history and epidemiological analysis, Methicillin-Resistant Staphylococcus aureus (MRSA) may be categorized into healthcare-associated or community-associated. Healthcare-associated MRSA (HA-MRSA)
 This type of MRSA is endemic in the local healthcare environment
including hospitals, extended care facilities and old age homes since the mid-1980s (3;4;9). The HA-MRSA tends to be isolated in patients who are hospitalized for more than 48 hours. Since MRSA carriage may persist for many months after a previous acquisition, HA-MRSA also include those isolates that are found at admission (or within 48 hours) from patients who possess risk factors for their carriage including hospitalization in the previous 1 year, recent
surgery, old age home residence, renal dialysis and exposure to invasive devices and employment in a healthcare institute (10;11).
 In Hong Kong, 30-50% of all hospital S. aureus isolates are
currently resistant to methicillin. The proportion of MRSA increased to 70-80% among isolates from intensive care units (ICU). In 1999, a study involving ICUs in 11 public hospitals showed 12% of the patients were MRSA carriers at ICU admission and that new acquisition of MRSA occurred in about 12% of the patients who were non-carriers initially (12).
 Most HA-MRSA also encode a battery of other resistance genes, they
are thus multiresistant to drugs in other antibiotic classes including
aminoglycosides, macrolides, fluoroquinolones and clindamycin (3;12).
Community-associated MRSA (CA-MRSA)
1. Patients infected with CA-MRSA do not have the usual risk factors
associated with HA-MRSA. In overseas countries, CA-MRSA were found to be more common among certain populations: children with chronic skin condition, prisoners, military personnel, aboriginals, injection drug users, the homeless and contact sports athletes (13-16); but such associations have not been observed among the CA-MRSA cases in Hong Kong.
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2. This organism often remains susceptible to antibiotic classes other
than beta-lactams, including clindamycin, aminoglycosides,
tetracyclines and fluoroquinolones.
3. The genotypes of CA-MRSA are different from the local nosocomial
strains. Most CA-MRSA strains in Hong Kong represent members in clonal cluster 30, similar to the situation in the Southwest Pacific region (17).
4. CA-MRSA possesses novel types of methicillin-resistance cassette
elements: type SCCmec IV or V, which are rare among the HA-MRSA strains.
5. CA-MRSA is more likely to encode the virulence factor, Panton-
Valentine leukocidin (PVL) toxin, which is associated with skin/soft tissue infections and severe necrotizing pneumonia (18).
VRE here refers to E. faecium and E. faecalis with resistance to glycopeptides (vancomycin MIC ≥8 μg/mL or teicoplanin MIC ≥16 μg/mL). The incidence of VRE in Hong Kong is low at present. The first isolate of VRE (E. faecium) in Hong Kong was imported in 1997. In the
subsequent 3 years, a few sporadic cases were identified in five hospitals including a small cluster recently in TMH. By the end of March 2001, about 10 cases of VRE have been detected, including both vancomycin-resistant E. faecium (vanA and vanB) and E. faecalis (vanA) (19). In a multicentre surveillance of 1600 consecutive patients
hospitalized in >10 ICUs in 1999, the prevalence was found to be <0.1%.
ESBL-producing EnterobacteriaceaeExtended-Spectrum Beta-Lactamases (ESBLs) are any bacterial enzymes that are capable of inactivation of third generation
cephalosporins. The term is most commonly used to refer to a group of bacterial enzymes that are derived from the classical beta-lactamases TEM-1, TEM-2 and SHV-1. In recent years, the "CTX-M" type of ESBL is also emerging in several Asian countries including China and Hong Kong SAR (20-22).
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ESBL may lead to therapeutic failures despite apparent susceptiblity to some third generation cephalosporins in
conventional antibiotic sensitivity testing methods. The ESBLs confer variable levels of resistance to cefotaxime, ceftazidime, other broad-spectrum cephalosporins, and to monobactams such as aztreonam, but had no detectable activity against the carbapenems (such as imipenem, ertapenem and meropenem).
If antibiotic therapy is indicated (colonization do not need any treatment other than infection control), serious infections by ESBL-producers should be regarded as clinically resistant to all the cephalosporins (including cefepime).
The ESBLs are usually encoded on genes in plasmids and because of the ready transmissibility of the responsible plasmids, dissemination of the resistance genes to other micro-organisms occur readily. Since genes encoding resistance to multiple antibiotics are often present in the same plasmid, co-transfer of multiple resistance to non-beta-lactam drugs, such as aminoglycosides, cotrimoxazole, chloramphenicol, and tetracycline is common.
At present, the prevalence of ESBLs among Enterobacteriaceae
isolated in many tertiary hospitals around the world is over 10-15%. In Hong Kong, a survey of four hospitals in 1997/98 (1200 non-duplicate clinical isolates) revealed rates of 6-23% for Klebsiella pneumoniae and 9 -14% for E. coli. (23).
Numerous outbreaks due to ESBL-producing bacteria have been
reported. Known risk factors for colonization and/or infection with organisms harbouring these enzymes include admission to an intensive care unit, recent surgery, instrumentation, prolonged hospital stay and antibiotic exposure, especially exposure to third generation cephalosporins.
Incidence of ESBLs can decrease after changes in antibiotic policy (mainly reducing the use of third generation cephalosporins) and enforcement of barrier precautions (Table 5).
Most CTX-M, TEM- and SHV-derived ESBLs are susceptible to
inhibition by the beta-lactamase inhibitors and theoretically beta-lactam/beta-lactamase inhibitor combinations should be active against these isolates. It must be remembered that production of ESBL doesn't preclude other mechanisms of resistance. In a recent survey, it was found that 40-70% of the ESBL-producing
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Enterobacteriaceae were resistant to amoxicillin-clavulanate,
ampicillin-sulbactam, ticarcillin-clavulanate, piperacillin-tazobactam and cefoperazone-sulbactam (20).
Enterobacter spp.
De-repression of AmpC beta-lactamase occurs most frequently among Enterobacter spp. De-repressed mutants are resistant to all the first, second and third generation cephalosporins.
AmpC-mediated resistance usually cannot be reversed by the currently available beta-lactamase inhibitors. Hence, most de-
repressed mutants are also resistant to ampicillin-sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam, ticarcillin-clavulanate, and cefoperazone-sulbactam.
It should be noted that resistance may develop in 20-40% of serious Enterobacter infections during treatment with a second or
third generation cephalosporin (refer to Part V for treatment recommendations).
In Hong Kong, a recent study found AmpC de-repression in 23% of all Enterobacter spp. (21). It was also found that ESBL of the CTX-M type may be emerging in some Enterobacter spp., such as E. hormaechei. Therefore, laboratories should pay attention to speciation of Enterobacter and be alert to the possibility of ESBL production in this genus.
Multidrug-resistant Pseudomonas aeruginosa
1. Pseudomonas aeruginosa, a saprophyte widely distributed in nature
and moist habitats (e.g. sinks, respiratory equipment, antiseptic or detergent solutions found in hospitals), is being increasingly recognized as a nosocomial pathogen, especially among critically ill or immunocompromised patients. Cross transmission or acquisition among patients likely occurs through hands of healthcare workers, or via contaminated fomites.
2. Under increasing antibiotic selection pressure, P. aeruginosa could
acquire increasing drug resistance, leading to emergence of multi-drug-resistant phenotype (MRPA). By definition, MRPA isolates
exhibit beta-lactam multiresistance (piperacillin, piperacillin-
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tazobactam, ceftazidime, cefepime, carbapenems), along with resistance to aminoglycosides and quinolones (24-26); underlying
mechanisms include enhanced production and dissemination of novel beta-lactamases, decreased outer membrane permeability, and presence of drug efflux pumps (27;28).
3. During the past 10 years, there have been numerous reported
outbreaks of MRPA worldwide (29-33). According to the recent global SENTRY surveillance conducted in 1997-1999, the rates of MRPA (defined as being resistant to piperacillin, ceftazidime, imipenem, and gentamicin) occurrence were as follows: Latin America, 8.2%; Europe, 4.7%; United States, 1.2%; Asia Pacific,
1.6%; and Canada, 0.9% (34). More recent reports indicate that the overall prevalence of MRPA continues to be on the rise, especially in tertiary care institutions (35;36). The exact prevalence of MRPA in Hong Kong is currently not known.
4. In patients suffering from chronic chest conditions (e.g. cystic
fibrosis), MRPA infection occurs after chronic airway colonization (37); other patients appear to acquire the infection after hospitalization. MRPA is predominantly isolated from respiratory samples (35;38). Risk factors for nosocomial MRPA acquisition and infection included: old age; severe underlying disease and / or being
bedridden (39); having maxillary sinusitis; high lung injury score and / or need for prolonged mechanical ventilation (40;41); various forms of instrumentation (e.g. urinary catheters and nasogastric feeding tubes (39;39), long dwelling central venous catheters (41). Prolonged use of antipseudomonal antibiotics such as beta-lactams, carbapenems, and fluoroquinolones is also important risk factor (38-41).
5. Treatment of MRPA infections is extremely difficult (42;43), because
MRPA can be resistant to all the currently available anti-
pseudomonal antibiotics, and may necessitate the use of unlicensed and potentially toxic drugs such as colistin and polymyxin B, or experimental combinations (44-46). Unfortunately, the new antibiotics (such as glycylcyclines and ketolides) in the pipeline are not active against MRPA. In view of this, MRPA infected or colonized patients should be nursed in single rooms whenever feasible and that all attending staff should practise hand hygiene for every patient contact and other necessary standard and contact precautions.
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Part II: Antimicrobial stewardship programme
Part II: Antimicrobial stewardship programme
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Part II: Antimicrobial stewardship programme
Antimicrobial stewardship program: summary
 The present summary is based on an article in the Hong Kong
Medical Journal (47).
 Antimicrobial drug resistance is now an important public health
threat because it endangers our ability to effectively treat infections. A multi-faceted approach involving the continuous application of a package of interventions should be implemented at regional and international levels. In healthcare settings, the recommended measures include infection prevention, effective diagnosis and early
treatment, using antimicrobials wisely and breaking the chain of transmission (Centers for Disease Control and Prevention, 2003). In the local settings, studies have found that there are rooms for optimization of antimicrobial prescriptions in the hospitals. Research conducted in the recent years further indicates that improvement in the pattern of prescriptions is feasible and can be implemented by means of antimicrobial stewardship programme (ASP) in a safe, scientific and professional manner. As antibiotic-resistant bacteria become more widespread, such initiatives will be assuming increasingly important roles. Therefore, the Scientific
Committee on Infection Control in the Centre for Health Protection recently come up with a document on "Optimizing antimicrobial prescriptions in hospitals by antimicrobial stewardship programme in Hong Kong: consensus statement". The present text summarizes the document under six broad questions:
1. What is the definition for optimal antimicrobial use?
 Optimal antimicrobial use (prudent prescribing) has been defined as
"the cost-effective use of antimicrobials which maximizes their
clinical therapeutic effect, while minimizing both drug-related toxicity and the development of antimicrobial resistance" (48;49). This implies usage in the most appropriate way for the treatment or prevention of human infectious diseases, having regard to the diagnosis, evidence of clinical effectiveness, likely benefits, safety, cost, and propensity for the emergence of resistance. Therefore, optimal antibiotic use means both "less" use (i.e. less unnecessary use), and "appropriate" use (i.e. not only the right antibiotic but also the right dose, route and duration to effect a cure while minimizing side effects and development of resistance according to the up-to-
date knowledge).
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2. What is the rationale for optimizing antimicrobial use?
 There are growing concerns about antimicrobial resistance. As
antimicrobial resistance increases, many previously time-honored, first-line therapies are rapidly losing their efficacies and are becoming obsolete (49). Antimicrobial resistance adds substantially to our already rising healthcare costs, prolongs periods during which individuals are infectious, increases morbidity, increases length of hospital stay, and even mortality.
 In developed countries, studies have found that 30-40% of
hospitalized patients were treated with antimicrobial agents. When antimicrobial usage was studied, there are large variations in the
pattern of usage (50;51) and half of the usage could be classified as suboptimal using recommended quality indicators (52;53). It is clear that suboptimal use not only adversely affects patient outcome (54;55), but also increases the risk of developing antimicrobial resistance (52;53;56;57).
 Currently, the issue of antimicrobial resistance is complicated
further by an insecure supply of new agents (58-60) and a dwindling number of companies investing in antimicrobial agents (61). Despite the dramatic rise of antimicrobial resistance in the past five years, only two new classes of antibiotics were approved
since 2000: oxazolidinones (linezolid) and the cyclic lipopeptides (daptomycin). In 2004, there are few novel antibacterial agents in the pipeline. Thus, improving the use of existing antibiotics by all clinicians is imperative.
3. What is antimicrobial stewardship programme? Who are the advocacies? (Table 3)
 The term antimicrobial stewardship is defined as the optimal
selection, dosage, and duration of antimicrobial treatment that results in the best clinical outcome for the treatment or prevention of infection, with minimal toxicity to the patient and minimal impact on subsequent resistance (62). In practice, this involves prescribing antimicrobial therapy only when it is beneficial to the patient, targeting therapy to the desired pathogens and using the appropriate drug, dose, and duration. Thus, ASP should not be
viewed simply as reduced use or a strategy for cost containment. Instead, by minimizing exposure to drugs, performing dose adjustments, reducing redundant therapy and targeting therapy to
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the likely pathogens, such activities can be viewed as a strategy to enhance patient safety.
 ASP involves a multidisciplinary, programmatic, prospective,
interventional approach to optimizing the use of antimicrobial agents. The multidisciplinary team typically includes clinical microbiologists, infectious diseases specialists, infection control practitioners, and clinical pharmacists. Having members from other medical specialties, such as surgery and paediatrics, is also recommended. Multiple approaches have been employed to enforce hospital policies to limit or control antimicrobial use (Table 3). Under the auspice of ASP, several behavioural methods have been
used successfully to effect changes, including problem-based education, consensus guidelines, peer review, concurrent review, data feedback, computer-based reminders, financial incentives, and the use of opinion leaders (63;64).
 Many professional societies and public health guardians including
the World Health Organization, Infectious Diseases Society of America (IDSA), Alliance for the Prudent Use of Antibiotics (APUA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH) are supportive of programmes that promote optimal antimicrobial use
(65;66). A few have even gone a step forward with action plans (48;65-67).
4. Is there evidence that ASP is beneficial? How did people document the benefits of the programme? Is there any evidence that it leads to better and more optimal antibiotic use in the hospital setting?
 Most studies found this strategy effective in reducing the usage of
targeted antibiotics and in controlling antimicrobial expenditures. In
terms of its impact on antimicrobial resistance, programmatic interventions in hospitals have yielded mixed results (68;69). The reason for this is that the factors promoting resistance are complex and multiple. It is clear that strong relationship exists between certain antibiotic classes and multi-drug resistant pathogens such as vancomycin with VRE; third generation cephalosporins with ESBL; and fluoroquinolones with MRSA and MRPA. At an institutional level, programmes designed to limit utilization of agents that exert greater effect on the above were successful in reducing the specific resistance rates.
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 Measurement and monitoring is an essential part of the programme.
After an initial implementation of a restricted formulary and antimicrobial approval system as part of an antimicrobial control programme, the team should meet regularly to review and update
the formulary, assess its effectiveness, provide and coordinate ongoing physician education, and analyze antimicrobial utilization data within the hospital. The programme should be dynamic, and continually reassessed, adding new components or deleting unsuccessful components over time.
 To allow for accurate intra- and inter-institutional comparison,
confounding differences in expenditure related to acquisition costs and variations in the amount of individual antibiotic used for individual patients should be corrected by appropriate standardization using the defined daily dose (DDD) and rates
calculated in terms of DDD per 1,000 admissions and DDD per 1,000 bed-days.
5. Is this the right time for Hong Kong to introduce ASP? Are we too early, or are we too late, and why?
 In Hong Kong, few would dispute the threat from antimicrobial
resistance and the needless expenditures associated with excessive antimicrobial use (70). Recent surveys show that suboptimal antimicrobial prescriptions may be commonplace in our hospitals
(71), and that they could be improved. In the two university hospitals, one prospective study in 2003 found that 76% of antibiotic prescriptions for patients hospitalized for exacerbation of chronic obstructive pulmonary disease were unjustified according to the prevailing Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (71). In 2004, real-time audit of "big gun" antibiotics in two hospitals have revealed that 20-25% of the prescriptions were not justified or suboptimal. The most common problems include treatment of colonization, narrower and equally
effective alternative or less toxic alternatives not being used and inappropriate duration (Seto WH, personal communication). In another prospective study of antibiotic combinations over a six-month period, it was found that one of the agents was redundant in 80% of 200 prescription episodes (71).
 More actions are required in areas where the antimicrobial
resistance problem is most serious. In Hong Kong, there is evidence that antibiotic resistance in some important nosocomial pathogens
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is worse than in many other parts of the world (72). In the United States, a "Public health action plan to combat antimicrobial
resistance-action plan" was developed in 1999. In the United Kingdom, significant progress has been made in optimizing the clinical use of antimicrobials since 2000 in terms of governmental directives, strategy and action plan (67;73). Recently, similar initiatives have been launched in Taiwan and South Korea at a national level. It is, therefore, definitely not premature to introduce such a "universal" and "continuous" programme to the public hospitals in Hong Kong.
 Many studies have found that optimization of antibiotics in
hospitals was feasible, safe and effective. A diversity of approaches have been reported and the experience accumulated so far indicates a multi-faceted "stewardship" and "immediate concurrent feedback" approach has clear advantages (62;74-81).
6. What are the disadvantages for having ASP? What problems have been reported? Are there any arguments against having ASP in the literature? Is there a role for an alternative mechanism? (Table 4)
 ASP involves proactive monitoring and feedbacks. One alternative
approach is "no control" (i.e. only by passive means). Such an approach relies heavily on the distribution of national guidelines. As discussed in detail in an international workshop, such a strategy has not worked in the past (82). Guidelines are seldom studied thoroughly by clinicians, and even if they are read, they rarely are incorporated into everyday practice. On the other hand, there are barriers and concerns to ASP that need to be addressed (Table 4). The perception of "threatened physician autonomy" can be a significant impediment to the effort. Previous studies and local
experiences have indicated that this is often an "emotional" response that can be resolved by immediate concurrent feedback, consensus building, involvement of institutional opinion leaders, and attention to process measures (83-85). In fact, similar programmes have been launched successfully in some Hospital Authority hospitals for the other drugs, including the statins, calcium channel blockers and acid suppressive agents.
 Another impediment is the incorrect perception that antimicrobial stewardship programmes are solely cost-driven and that patient safety may be at risk. In this regard, recent
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reports have emphasized the inclusion of quality indicators such as time to reception of appropriate empirical antibiotics. Other
suggested indicators include: (a) clinical outcomes of bacteraemia due to Gram-negative organisms (86), (b) mortality for all patients, for those treated with antimicrobials, and for those suffering from infections, (c) duration of hospital stay for all patients and for those treated with antimicrobial drugs, and (d) re-hospitalization rate within 30 days after discharge for all patients and those treated with antimicrobial drugs (81). As in any quality improvement programme, a financial incentive is important to secure support by the hospital management. This is no exception for antimicrobial
stewardship programme. Good leadership and effective communications are essential to keep members, prescribers and patients to the appropriate focus. This could be enhanced by having a multidisciplinary steering committee, and by regular use of data feedback on the patterns of usages, patient outcomes, and antimicrobial resistance data. In principle, member in the committee should have a strong sense of commitment and cooperation. The composition of the multidisciplinary steering committee may be unique to each institute.
Conclusion
 Considering the broader perspective, working targets are needed
and the programmes should be regularly evaluated. For a start, each hospital will need to form a steering group and to lay down the institutional priorities. In the literature, programme models are available for optimizing the uses of aminoglycosides, vancomycin, broad-spectrum antibiotics, antibiotic combinations, and for switching therapy from intravenous to oral. It is clear that a multi-faceted approach incorporating immediate concurrent feedback is
most likely to be successful. In order to safeguard health care quality, the use of quality indicators and timely feedback of data are essential. Our fight against antimicrobial resistance is going to continue. Hence, a major challenge will be how to keep the programmes viable and sustainable within our system in the longer terms.
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Table 3. Methods to implement antimicrobial control 1. Written hospital guidelines.
2. Educational efforts aimed at changing prescribing practices of
3. Providing consultation from clinical microbiologist/infectious
diseases specialist.
4. Restriction of hospital formulary through the Drug and
Therapeutics Committee.
5. Utilization review with guidelines for rational and appropriate
6. Ongoing monitoring and analysis of antimicrobial agents
7. Ongoing surveillance of antimicrobial susceptibility.
8. Monitoring adherence to advice on choice of antimicrobial
9. Usage feedback to physicians.
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Table 4. Potential barriers to reaching the strategic goals Barrier Countermeasures and improvement strategies Ownership and accountability
1. Lack of ownership and
1. Designate responsibility and
accountability for recognizing and
accountability for the process.
reporting trends.
2. Set up a multi-disciplinary team to
2. Failure to integrate work of
develop a collaborative system and
laboratory, infection control,
monitor results.
medical, nursing, and intensive
care-unit staffs.
Staff knowledge and practice
1. Lack of time for the laboratory
1. Ensure adequacy of laboratory and
and/or infection control staff to
infection-control staffing and prioritize
generate and analyze data.
activities of staff so that data can be
2. Lack of time for healthcare
generated and analyzed.
providers to examine and discuss
2. Report data in an easy-to read/interpret
data and inconsistent or
format and, when appropriate, include
erroneous interpretation of data
data interpretation in the report.
Physician attitudes
1. Lack of trust in the hospital
1. Use a data-driven approach to cultivate
trust; e.g. communicate regularly with
physicians about trends in antimicrobial
usage, cost, and resistance; feedback to
individual physicians their performance
Expertise
1. Lack of expertise in biostatistics
1. Ensure availability of consultants,
(e.g. presenting trends and
especially when designing analytic
analyzing data).
strategy and interpreting trend data.
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State-of-the art: Limiting antimicrobial resistance
US surveys: 22-65% usage of antibiotics in the hospitals is
Outbreaks of multi-resistant bacteria, including those that persist despite apparently adequate infection control measures, can be limited effectively by antibiotic programme directed at judicious use of antibiotics.
While restriction of an individual antibiotic (such as cefotaxime or ceftazidime) has been reported to be useful in controlling outbreaks of drug-resistant bacteria, the general consensus is that the main focus should be directed at the rational use of all
classes of antibiotics rather than merely restricting the use of individual drugs (6;86-96).
Over-prescription of third generation cephalosporins and vancomycin
Experience from several overseas centres suggests that over-prescription of third generation cephalosporins and glycopeptides are closely associated with the selection and dissemination of ESBL-producing Enterobacteriaceae, de-repressed AmpC-type mutant among Enterobacter cloacae, Citrobacter freundii, Serretia marcescens, MRSA,
Cephalosporin use has been identified as a risk factor for enterococcal colonization and superinfection, as well as for
antibiotic-associated diarrhea, the main reason for oral vancomycin (97;98).
Significant risk factors for colonization or infection with VRE were prior antibiotic use (p=0.04), the previous use of third-generation cephalosporins (p=0.03), and the previous use of parenteral vancomycin (p=0.002). This data was obtained from 7 hospitals including primary and tertiary care facilities (200-700 beds) (99).
In the Cornell University Medical College, New York, it was found that the duration of hospitalization, intrahospital transfer
between floors, use of antimicrobials (i.e. vancomycin and third generation cephalosporins), and duration of vancomycin use (≥7
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days) were independently associated with VRE infection or colonization (100).
Ten weeks after the introduction of cefotaxime, resistant Enterobacter cloacae could be isolated from stool cultures in an
increasing proportion of patients and septicaemia developed in 6 cases (101).
In 6 US hospitals, previous administration of third-generation cephalosporins was more likely to be associated with multi-resistant Enterobacter isolates in an initial positive blood culture
(69%) than was administration of antibiotics (20%) that did not include a third-generation cephalosporins (p<0.001) (102).
Resistance to third generation cephalosporins among Enterobacter spp, Citrobacter freundii, Morganella morganii, Serratia marcescens and Providencia spp. has become widespread
both locally within hospitals and nationally. This trend has been shown to correlate closely with the extent of usage of some third generation cephalosporins (1;103).
Decreased antibiotic resistance after changes in antibiotic use
No simple answer exists on the control of multi-drug resistant
bacteria. The traditional approach slanted heavily on infection control measures, which are obviously important but can be difficult to implement. When audited, compliance with hand hygiene measures has been consistently low (<40%) (104). Outbreaks of multi-drug resistant bacteria have continued despite apparent adherence to "standard" hygienic measures. In recent years, there has been renewed interest on the strategic use of antibiotics as a measure for prevention or control of antimicrobial resistance (94). In fact, several studies have demonstrated that strategic use of antibiotics (so far, only class
restriction of the cephalosporins have been evaluated to a significant extent) can lead to:
Less multi-resistant de-repressed AmpC-type Enterobacter spp. An outbreak of infections by multi-resistant Enterobacter spp.
disappeared after use of cefotaxime was discontinued in the unit.
Less ESBL-producing Enterobacteriaceae. Literature on antimicrobial strategies as an intervention to reduce ESBL-producing K. pneumoniae was summarized in Table 5. In a case-
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control study, the use of beta-lactam/beta-lactamase inhibitor combination was shown to be a protective factor (105).
Less vancomycin-resistant enterococci. Two studies reported on the successful control of VRE outbreaks by changing antibiotic
usage (92;106). In one medical centre (92) , the antibiotic formulary was altered by restricting the use of cefotaxime and vancomycin and adding beta-lactamase inhibitors to replace third-generation cephalosporins. After 6 months, the average monthly use of cefotaxime, ceftazidime, vancomycin, and clindamycin had decreased by 84%, 55%, 34% and 80% respectively (p<0.02). The point prevalence of faecal colonization with VRE decreased from 47-15% (p<0.001). In another haematologic unit (106), acquisition of VRE paralleled the use of
ceftazidime as empirical therapy for neutropenic fever. Phase 1: ceftazidime as empirical therapy, VRE carriage rate was 57%. Phase 2: piperacillin-tazobactam replaced ceftazidime as empirical therapy, VRE carriage decreased to 8%. Phase 3: ceftazidime re-introduced as empirical therapy, VRE carriage increased to 36%. Those who are interested in the experimental data that might explained this observed relation between VRE, cephalosporins and BLBLI should refer to a recent review by Rice et al (107).
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Table 5. Summary of published data on antimicrobial strategies as an intervention to reduce ESBL resistance.Year period (Ref)
Setting (type of study)
Intervention/result
Other observations
Epidemic rise in ESBL in K.
Minimize use of ceftazidime
ESBL rate remain
pneumoniae from 6-28% within 1
(marked and sustained ↓);
<10% next 4 years
year in a medical centre
addition of piperacillin-
(intervention study)
tazobactam to formulary (usage ↑)
Spread of VRE in one institute
Use of BLBLI emphasized and the
Mean incidence of
Cefotaxime-resistant
continued despite infection control
use of 3GCs, vancomycin and
Acinetobacter ↑ by
measures (intervention study).
clindamycin restricted; addition of
ampicillin-sulbactam and piperacillin-tazobactam to
Outbreak of CRKP in one medical
Ceftazidime was replaced by
CRKP ↓ from >30%
centre. Use of ceftazidime ↑ 600% in imipenem.
the 2 years before outbreak
(intervention study).
A clonal outbreak of ESBL-
Restriction of 3GC (usage ↓ by
ESBL carriage ↓ from
producing K. pneumoniae in an ICU
87% after intervention).
33 to 40% to 0%.
(intervention study).
An outbreak of ESBL-producing K.
Class restriction of cephalosporins CRKP ESBL ↓ by
Imipenem-resistant
pneumoniae in a hospital since
(usage ↓ by 80% after
P. aeruginosa ↑ by
1990 (intervention study).
intervention). Usage replaced by
Clonal outbreak of CRKP in hospital Physician education on
Hospital A: CRKP ↓
% KP resistant to
A. Polyclonal outbreak of CRKP in
association of ↓ ceftazidime use
BLBLI also ↓ (36 to
hospital B (intervention study).
and ↓ CRKP. Use of ceftazidime ↓
Hospital B: CRKP ↓
by 71% (hospital A) and 27%
3GC, third generation cephalosporins; BLBLI, beta-lactam/beta-lactamase inhibitor; CRKP, ceftazidime-resistant K. pneumoniae.
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Classification of therapy

Empirical therapy In the clinical situation of "empirical use", the antimicrobial(s) is/are
used as initial therapy directed to eradicate the most likely pathogens. Before initiation of antimicrobials, appropriate specimens for stains and culture of microorganisms should be obtained. Results of identification and susceptibility of microorganisms are likely to be available in the following 48 to 72 hours. The use of broad-spectrum antibiotics or combination therapy is usually necessary to cover the different organisms capable of causing an infection. In general, the use of agents in this situation should not extend beyond the time required to obtain results of cultures and susceptibility. Choice of agent(s): based upon adequate coverage of the potential pathogens of the potential infection sites and the anticipated antimicrobial susceptibility patterns of the bacterial isolates. Recommendations of empirical therapy for some common infections are outlined in Part IV. Known-pathogen therapy In the clinical situation of known pathogen use, the antimicrobial(s) is /are used when the microbiology laboratory has identified the micro-organism causing the infection and the susceptibility pattern is known. If during empirical use, the patient is started on combination therapy or broad spectrum antibiotics, the antimicrobial spectrum should be narrowed to cover the micro-organisms identified as the aetiologic agent. Streamlining from broad-spectrum to specific, narrow spectrum antimicrobials helps to avoid colonization with resistant organisms and superinfections. In the absence of allergy or other contraindications, the agent (appropriate for the site and type of
infection) with the narrowest spectrum in a group or a list of candidate drugs should be used. It should be noted that the skin and mucous membrane surface of the hospitalized patient are often colonised with nosocomial bacteria (such as MRSA, E. coli, Klebsiella spp, etc.), systemic antimicrobial therapy
(both IV and PO) should not be administered in an attempt to eradicate these micro-organisms.
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Switch therapy-conversion from IV to PO In the clinical situation of switch therapy use, PO antimicrobials
replace IV usage for completion of therapy. IV is almost always employed in serious infections to ensure maximal serum/tissue levels. With few exceptions such as meningitis, infective endocarditis, the majority of patients with infections do not require completion of the antimicrobial course with IV therapy. The following criteria have been developed for transition from IV to PO antimicrobial (114;115):
1. Patient with no clinical indication for IV therapy.
2. Patient is afebrile for at least 8 hours.
3. The WBC count is normalizing (falling towards or <10x109/L).
4. Signs & symptoms related to infection are improving.
5. Patient is not neutropenic (neutrophil count >2 x109/L).
6. Patient is able to take drugs by mouth (non-NPO).
7. Patient with no continuous nasogastric suctioning.
8. Patient with no severe nausea or vomiting, diarrhea,
gastrointestinal obstruction, motility disorder.
9. Patient with no malabsorption syndrome.
10. Patient with no pancreatitis or active gastrointestinal bleeding or
other conditions that contraindicated to the use of oral medications.
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Table 6. Strategies for optimization of antimicrobial therapy Stages in the management of infection Strategies for optimization Empirical therapy (ET)
• Document the presence of infection
• Likely pathogens?
• Collection and analysis of local
• Likely susceptibility pattern
• Community- or hospital-acquired
• Pocket reference guide
• Monotherapy or combination therapy?
When culture and susceptibility results are available
Known-pathogen therapy (KPT)
• Narrowest spectrum according to
• Cascade reporting of sensitivity
laboratory results
• Daily review of prescription of
• Follow guidelines on the judicious use of
"big gun" antibiotics by ASP
ceftazidime, imipenem/ertapenem/
meropenem, vancomycin/teicoplanin/
• Daily reporting of deviations
from guidelines to clinical
microbiologist/ID physician
• ASP team to give daily
immediate concurrent feedback (ICF) to prescribers.
Switch therapy (116;117)
• A switch from intravenous to oral therapy • Daily review of patients on IV
• Criteria for switch therapy
"big gun" antibiotics by ASP
• Clinical diagnosis compatible with oral
• Daily recommendation for
• Patient has functioning gastrointestinal
"switching" by ASP team
• Patient is afebrile (for >24h) • Signs and symptoms related to infection
are improving or resolved
• The WBC count is normalizing
Stop therapy
• Type of infection
• Clinical responses • Follow-up culture results where
IMPACT Third Edition (Version 3.0)
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Part III: Guidelines for selected antimicrobials use
IMPACT Third Edition (Version 3.0)
Part III: Selected Antimicrobial agents
Vancomycin Situations in which the use of vancomycin/teicoplanin is appropriate (6;83)1.
Treatment of serious infections caused by beta-lactam resistant Gram-positive bacteria (e.g. MRSA, coagulase-negative staphylococci).
Treatment of infections caused by Gram-positive bacteria in patients who have serious allergies to beta-lactam antimicrobial agents (e.g. anaphylactic reaction, Stevens-Johnson syndrome).
When Clostridium difficile colitis fails to respond to metronidazole
therapy or is severe and life-threatening.
As prophylaxis for endocarditis following certain procedures in-
patients at high risk for endocarditis; according to recommendation from the American Heart Association. (e.g. as prophylaxis for genitourinary or gastrointestinal procedures in moderate or high-risk patients allergic to ampicillin/amoxicillin).
As prophylaxis for major surgical procedures involving the implantation of prosthetic material or devices in known carriers of MRSA. For elective procedures, daily washing of skin and hair with a suitable antiseptic soap (e.g. 4% chlorhexidine liquid soap) and topical treatment of the anterior nares with nasal mupirocin
ointment (for 5 days) are recommended before the procedures. Vancomycin may be less effective in preventing surgical wound infection due to methicillin-sensitive staphylococci (118).
Situations in which the use of vancomycin/teicoplanin are not advised 1.
Treatment of MRSA nasal carriage or colonization at other sites such as the isolation of MRSA from • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers
Routine surgical prophylaxis other than in a patient who has serious allergy to beta-lactam antimicrobial agents.
Routine empirical antimicrobial therapy for neutropenic fever (except as recommended by the IDSA 2002 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever).
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Treatment in response to a single blood culture positive for coagulase-negative staphylococci, if other blood cultures taken during the same time frame are negative.
Continued empirical use of presumed infections in patients
whose cultures (blood, joint fluid, peritoneal fluid, pus, etc), are negative for beta-lactam-resistant Gram-positive bacteria (e.g. MRSA).
Systemic or local (e.g. antibiotic lock) prophylaxis against infection (or colonization) of indwelling (central or peripheral) intravascular catheters.
As routine prophylaxis, before insertion of Hickman/Brovac catheter or Tenckhoff catheter.
As part of the regimen for selective digestive tract
decontamination.
Primary treatment of Clostridium difficile colitis, except when it is
severe and life-threatening.
10. Routine prophylaxis for patients on continuous ambulatory
peritoneal dialysis or haemodialysis.
11. Treatment (e.g. chosen for dosing convenience) of infection
caused by beta-lactam-sensitive Gram-positive bacteria in patients who have renal failure.
12. Use of vancomycin solution for topical application (e.g. to burn
wound, ulcers) or irrigation (e.g. of T-tube, drains).
Vancomycin dosage in special situations and therapeutic drug monitoring 1.
In adults, the standard recommended dose of vancomycin is 30 mg/kg/day (IV 1 g q12h or IV 0.5 g q6h in a normal 70 kg person).
Therapeutic drug monitoring (TDM) Vancomycin exhibits time-dependent killing. Efficacy can usually be assumed if the trough concentration is sufficiently above the MIC of the infecting organism (i.e. best if vancomycin levels at site of infection are maintained above MIC throughout the dose
interval). MIC of most susceptible organisms (e.g. MRSA) ranges 1-2 μg/mL. Routine TDM is not indicated in most patients because vancomycin pharmacokinetics are sufficiently predictable that safe and effective vancomycin dosage regimens (giving trough
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levels 5-10 μg/mL and peak levels <40 mg/mL) can be
constructed on the basis of patient's age, weight and estimated renal function. Indications for TDM (a) Renal impairment (rapid change/unstable renal function
making it difficult to estimate dose)
(b) ICU patients co-treated with dopamine and/or dobutamine
(c) Severe burn (120) (d) Morbid obesity (121) (e) Spinal cord injury (122) When TDM is indicated, check only trough level. There is no solid data to support the widely referenced trough range of 5-10 μg/mL and accordingly, serum concentrations have been selected somewhat arbitrarily, based on pharmacology, retrospective
studies, case reports and personal opinions. Due to the poor penetration of vancomycin to certain lung tissues, the 2005 ATS guideline recommend trough levels of 15−20 μg/mL for treatment of MRSA hospital-acquired pneumonia (123). Current literature does not support peak concentration measurement (124).
Dosage table/nomogram in patients with impaired renal function (Table 7) • An initial single dose of 15 mg/kg should be given to achieve
prompt therapeutic serum concentration. Subsequent daily maintenance dose is to be determined according to dosage
• The dosage table/nomogram is not valid for functionally
anephric patients on dialysis. For such patients, the dose required to maintain stable concentrations is 1.9 mg/kg/day ( 130 mg/day for a 70 kg person).
• For patients with marked renal impairment, it may be more
convenient to give maintenance doses of 0.25 g to 1 g every 3-7 days.
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Table 7. Dosage table for vancomycin Creatinine clearance ( mL/min) Vancomycin dose (mg/24 h)
Adapted from vancomycin package insert July 2004 .
morbidly obese patients (121;125) (Table 8)
• Serum clearance of vancomycin in morbidly obese patients
was 2.3-2.5 times higher than that observed in non-obese subjects (121;126).
• In a study of 24 morbidly obese patients, the mean (±SD)
vancomycin dose required to achieve steady state peak 25-35 μg/mL and trough 5-10 μg/mL were 1.9 g (±0.5 g) q8h.
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Table 8. Calculation of vancomycin dosage for morbidly obese patient

Scenario: Female/30yr, Calculation body weight 200 kg, height 1.8 m, serum creatinine 80 μmol/L
Determine if the patient is TBW/IBW ratio:
0.8−1.25 = normal >1.25−1.9 = obese >1.9 = morbid obesity
Determine dose of
30 mg/kg TBW/day
6 g per day if normal
(administer as IV 2 g q8h; infuse each 2 g dose over at least 2 h)
Estimate creatinine
Cockcroft-Gault formula
clearance (CrCl)
not accurate in morbidly obese patients. The Salazar-Corcoran equation appears to give
the least biased estimate of CrCl
Monitor trough level
Target trough at 5-10
Adjust dosing interval
according to trough level
Ideal body weight (IBW) • IBW for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each
inch over 5 feet)
• IBW for female = 45.5kg + 0.9 kg for each cm over 152 cm (2.3 kg for
each inch over 5 feet)
Salazar-Corcoran equation (for estimate of creatinine clearance in morbidly
obese patients): Male patient, calculate CrCl as follows:
(137−age in years) × (TBW in kg × 0.285) + (12.1 × height in meter)
0.58 × serum creatinine in μmol/L
Female patient, calculate CrCl as follows:
(146−age in years) × (TBW in kg × 0.287) + (9.74 × height in meter)
0.68 × serum creatinine in μmol/L
a TBW, total body weight
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Quinupristin/dalfopristin and linezolid
Indications for linezolid (Zyvox) or quinupristin/dalfopristin (Synercid):
a. Infections by vancomycin-resistant enterococci (VRE) or S. aureus with reduced susceptibility to vancomycin (e.g. VISA)
b. Infections by methicillin-resistant Staphylococcus aureus in the
case of vancomycin failure (e.g. unexplained breakthrough bacteraemia) and/or serious allergy. In these complicated circumstances, the opinion of a specialist (microbiologist or ID physician) should be sought.
Most VRE (n=11) identified in Hong Kong so far are susceptible to linezolid (both E.faecalis and E. faecium) at ≤4 μg/mL and quinupristin/dalfopristin (E. faecium only, at ≤1 μg/mL) (19).
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Table 9. Comparison of linezolid and quinupristin/dalfopristin Linezolid
Yes/1999 (for serious infections
associated with vancomycin-resistant E. faecium)
IV/PO. Bioavailbility of PO
linezolid is 100%.
IV/PO 600 mg q12h
IV 7.5 mg/kg q8h (infuse over 1 h in D5)
catheter for administration
Activity vs. VRE
both vancomycin-resistant
Only vancomycin−resistant E. E. faecalis and E. faeciumfaecium a
Nil (No effect on 1A2, 2C9,
Inhibit 3A4 isoenzyme strongly,
cytochrome P450 2C19, 2D6, 2E1, 3A4)
hence interactions with midazolam, nifedipine, astemizole, terfenadine,
cyclosporin (must monitor level), tacrolimus
Yes (a weak, reversible,
Nil (No effect on MAO).
nonselective MAO inhibitor),
hence potential for
interactions with adrenergic and serotonergic drugs.
Thrombocytopenia (related
Phlebitis (high incidence if
to duration of treatment;
administered via peripheral
incidence 0.3-10%; need
vein); arthralgia/myalgia (dose
monitoring if treated for >7d) related; incidence 1.3-33%)
Compatible with both D5
Form precipitate with saline.
DO NOT flush with saline or heparin after quinupristin/
dalfopristin administration.
No adjustment in dose
No adjustment in dose required
required in pt. with renal
in pt. with renal impairment or
impairment. Give dose after
undergoing dialysis.
Data from package insert of Zyvox and Synercid. a All E. faecalis isolate (including vancomycin-resistant E. faecalis) are intrinsically resistant to quinupristin/dalfopristin.
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Ceftazidime Indications for using ceftazidime (Fortum) (127) 1.
Empirical therapy of neutropenic fever, either as monotherapy or
in combination with an aminoglycoside (128).
2. Therapy of infection by Burkholderia pseudomallei infection
(melioidosis). • Probable case (compatible chest X-ray plus a melioidosis titre
of ≥ 1/640) or definite case (isolation of B. pseudomallei).
Known pathogen therapy of documented infection by susceptible Pseudomonas aeruginosaa, such as: (a) Bacteraemia with isolation of Pseudomonas aeruginosa from
(b) Deep-seated infection with isolation of Pseudomonas aeruginosa from normally sterile body site or fluid (CSF, peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc) a.
(c) Nosocomial pneumonia, as defined by CDC guidelines
(appendix), with isolation of Pseudomonas aeruginosa in a
significant quantity, from a suitably obtained, good quality respiratory tract specimenb.
Footnotes
a For serious P. aeruginosa infection, an anti-pseudomonal beta-lactam should be given in combination with an aminoglycoside such as gentamicin given once daily for the initial 3 to 5 days to achieve synergistic killing. For susceptible isolates; anti-pseudomonal beta-lactams in decreasing order of preference: piperacillin or piperacillin-tazobactam or ticarcillin-clavulanate > cefoperazone or cefoperazone-
sulbactam or cefepime or ceftazidime > imipenem or meropenem.
b Colonization of the respiratory tract by P. aeruginosa, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of P. aeruginosa at the indicated quantity and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance): 1. 102-103CFU/mL or moderate/heavy growth for protected specimen brush. 2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage. 3. Moderate/heavy growth for tracheal/endotracheal aspirate specimens with ++
to +++ white cells and absent/scanty epithelial cells.
4. Expectorated sputum (as defined by the American Society for Microbiology)
with >25 WBC/low power field and <10 epithelial cells/low power field.
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Situations/conditions in which ceftazidime is not advised 1.
Treatment of colonization by Pseudomonas aeruginosa such as
the isolation of these organisms from • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers
Empirical or continued treatment of suspected or confirmed infection by S. pneumoniae including bacteraemia, pneumonia
and meningitis. • Infection outside the central nervous system by both penicillin-
susceptible and penicillin-non-susceptible (MIC <4 μg/mL), the drugs of choice are penicillin G (standard or high dose) or amoxicillin or cefotaxime or ceftriaxone (refer to known-pathogen therapy chart).
Empirical or continued treatment of infection by Enterobacteriaceae such as E. coli and Klebsiella spp. susceptible to other antimicrobial agents. • For susceptible isolates the beta-lactam of choice in
descending order of preference are as follows: ampicillin or amoxicillin > ampicillin-sulbactam or amoxicillin-clavulanate > cefuroxime > ceftriaxone or cefotaxime.
Empirical therapy of community-acquired pneumonia, including
patients hospitalized in the ICU for serious pneumonia and patients with structural disease of the lung (adapted from Infectious Disease Society of America 1998). • Other agents with activity vs. P. aeruginosa and S. pneumoniae
preferred because ceftazidime (while active vs. P. aeruginosa) is not useful vs. penicillin-non-susceptible S. pneumoniae.
Empirical or continued treatment of anaerobic or mixed infection in the head and neck, biliary, pancreatic, gastrointestinal, peritoneal, pelvic or peritoneal regions. • Ceftazidime has virtually no activity against most of the
medically important anaerobes.
Empirical or continued treatment of patients with colonization or infection by Enterobacteriaceae such as E. coli, Klebsiella spp. and Enterobacter spp. known to produce ESBL. • Applies irrespective of whether ceftazidime was tested or not
and also irrespective of the apparent in vitro susceptibility of the isolate to ceftazidime.
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Empirical or continued treatment of infection by S. aureus (both
Empirical or continued treatment of infection by all enterococci such as E. faecalis and E. faecium.
Empirical treatment for community-acquired meningitis.
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Indications for using imipenem/meropenem/ertapenem 1.
Therapy of infections attributed to ESBL-producing bacteria (such as E. coli or Klebsiella spp. ) such as: • Bacteraemia with isolation of ESBL-producing bacteria from
• Deep-seated infection with isolation of ESBL-producing
bacteria from normally sterile body site or fluid (CSF, peritoneal fluid, pleural fluid, joint fluid, tissue, pus, etc).
• Nosocomial pneumonia, as defined by CDC guidelines, with
isolation of ESBL-producing bacteria in a significant quantity, from a suitably obtained, good quality respiratory tract
Empirical therapy of neutropenic fever in high risk patients. (As Ertapenem has no anti-pseudomonal activity, it should not be used as empirical therapy for neutropenic fevers or for treatment of presumed/confirmed infections by the non-fermenters such as Pseudomonas aeruginosa and Acinetobacter.)
a Colonization of the respiratory tract by ESBL-producing bacteria, especially in mechanically ventilated patients is common. Antimicrobial therapy of colonization is not indicated. Isolation of ESBL-producing bacteria at the indicated quantity
and specimen type is suggestive of infection rather than colonization (in descending order of clinical significance): 1. 102-103 CFU/mL or moderate/heavy growth for protected specimen brush. 2. 103-104 CFU/mL or moderate/heavy growth for bronchoalveolar lavage. 3.
Moderate/heavy growth for tracheal/endotracheal aspirate specimens with
++ to +++ white cells and absent/scanty epithelial cells.
Expectorated sputum (as defined by the American Society for Microbiology) with >25 WBC/low power field and <10 epithelial cells/low power field.
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Situations/conditions in which imipenem/meropenem/ertapenem is not advised 1.
Treatment of colonization by ESBL-producing bacteria such as the isolation of these organisms from. • Surface swab of superficial wounds • Surface swab of chronic ulcers • Surface swab of pressure ulcers
Empirical therapy of most community-acquired infections including pneumonia, appendicitis, cholecystitis, cholangitis, primary peritonitis, peritonitis secondary to perforation of stomach, duodenum or colon, skin/soft tissue infections, etc.
As known-pathogen therapy for infections caused by organisms
susceptible to other beta-lactams.
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Once daily aminoglycosides 1.
Once daily aminoglycoside (ODA) dosing is as effective as multiple-daily dosing in most clinical settings. The former dosing
probably results in a lower risk of nephrotoxicity than the latter. With ODA, any differences in the relative nephrotoxicity of the aminoglycosides are likely to be small. Nonetheless, there is considerable confusion on the dose and how to monitor serum aminoglycoside levels when using ODA dosing.
Dosing to be based on actual body weight unless the patient is morbidly obese (i.e. 20% over ideal body weight, IBW). Aminoglycoside dosing weight for morbidly obsess patient = ideal body weight + 0.4 (actual body weight - IBW). Formula for calculation of ideal body weight is as follows: Ideal body weight for male = 50 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) Ideal body weight for female = 45.5 kg + 0.9 kg for each cm over 152 cm (2.3 kg for each inch over 5 feet) For patient with impaired renal function, give the first dose according to body weight as above. Subsequent frequency of administration (of the same dose) to be based on the estimated creatinine clearance of the patient according to the following table. Cockcroft-Gault formulaTo estimate creatinine clearance, calculate as follows Creatine clearance for male patient (mL/min) = (140-age) x 1.2 x ideal body weight (kg) /serum creatinine (μmol/L) (Female: 0.85 × above value) (Unit conversion for serum creatinine: mg/dL x 88.4 = μmol/L)
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Initial dosing interval a (mL/min)
20-40 q48h <20
Follow serial levels to determine time of
next dose (level <1 μg/mL)
a At present, the dosage of aminoglycoside to use in a ODA strategy
has not been clearly determined. Dosages for gentamicin, tobramycin and netilmicin have ranged from 3 to 7 mg/kg, and amikacin dosages have ranged from 11 to 30 mg/kg. On the basis of local experiences and a recent consensus meeting, the following doses are recommended for initial therapy in local Chinese: for gentamicin and tobramycin, 3.5 mg/kg; netilmicin, 4.4 mg/kg and amikacin, 15 mg/kg (129). 4.
Therapeutic drug monitoring (TDM) (130-132)
Routine TDM not indicated in patients under the following
conditions: (a) Receiving 24-h dosing regimen, (b) Without concurrently administered nephrotoxic drugs (e.g.
vancomycin, amphotericin B, cyclosporin),
(c) Without exposure to contrast media, (d) Not quadriplegic or amputee, (e) Not in the ICU, (f)
Younger than age 60 yr
(g) Duration of planned therapy less than 5 to 7 days.
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Part III: Selected Antimicrobial agents
If Therapeutic drug monitoring is indicated (e.g. due to impaired renal function), check level and interpret the result as follows:
a) For once daily (extended-interval) dosing, obtain a single blood
sample after the first dose between 6-14 h after the start of the infusion. Do not check pre- and post-dose.
b) Write down the time in number of hours after last dose in request
form (e.g. 8 h post-dose). This is essential for result interpretation.
c) When result becomes available, plot the value on the Hartford
normogram (Table 10) and work out the appropriate dosing interval by the following table. With this method, the size of each dose need not be reduced.
Post-dose level Dosing interval
Level falls in the area
Dose at an interval of every
Level falls in the area
Dose at an interval of every
Level falls in the area
Dose at an interval of every
Level on the line
Choose the longer interval
Level off the normogram at Stop the scheduled therapy, the given time
obtain serial levels to determine the appropriate time of the next dose
IMPACT Third Edition (Version 3.0)
Part III: Selected Antimicrobial agents
Table 10. Hartford Hospital once-daily aminoglycoside normogram for gentamicin and tobramycin The Hartford normogram has not been validated in the following category of patients: paediatrics, pregnancy, burns (>20%), ascites, dialysis, Enterococcal endocarditis (51).
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Summary of selected antifungal agentsTable 11. General patterns of antifungal susceptibility

Acute pancreatitis (Box 1 & 2) Moderately severe Very severe
Only Ranson ≥3
but no organ failure and
CRP ≥150 mg/L;
CRP <150 mg/L
CT proven pancreatic necrosis
IMPACT Third Edition (Version 3.0)
Part IV: Empirical therapy
Management of community-acquired pneumonia General considerations and principles1. A number of guidelines on the management of community-
acquired pneumonia (CAP) were released or updated recently. While these guidelines were drawn on the basis of the same set of literature, patient stratification and specific suggestions still vary quite a bit (157;172;173).
All agreed that S. pneumoniae is the most common pathogen in
CAP including those without an identifiable etiology. Hence, the choice of agents for empirical therapy should consider the regional data on prevalence and risk factors for drug-resistant S. pneumoniae (DRSP).
3. Appropriate antimicrobial therapy should be initiated within 8
hours of hospitalization. Prior studies indicated that compliance with this recommendation is associated with a significant reduction in mortality (174).
Factors to be considered in choosing empirical therapy for CAP:(a) Place of therapy (outpatient, inpatient ward, or intensive
(b) Role of atypical pathogens (e.g. Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella spp.) is increasingly
being recognized. ATS guidelines even suggested that all patients should be treated for the possibility of atypical pathogen infections (173).
(c) Presence of modifying factors including risk factors for
DRSP (e.g. age >65 yr., beta-lactam therapy within past 3 months, alcoholism, multiple medical comorbidities, exposure to a child in a day care centre), enteric Gram- negatives (residence in a nursing home, underlying cardiopulmonary disease, multiple medical comorbidities, recent antibiotic therapy), and P. aeruginosa (e.g. bronchiectasis).
5. Several antibiotics active against P. aeruginosa, including
cefepime, imipenem, meropenem, piperacillin, and piperacillin-tazobactam are also highly active against DRSP. They can be used for patients having specific risk factors for P. aeruginosa.
6. If a macrolide is relied upon for coverage of H. influenzae, the
newer macrolides (e.g. clarithromycin or azithromycin) should be used instead of erythromycin.
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For most patients, appropriately chosen initial antibiotic therapy should not be changed in the first 72 h, unless there is marked clinical deterioration.
8. Most patients with CAP will have an adequate clinical response
within 72 h. After the patient has met appropriate criteria, switch from iv to oral therapy can be made.
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Management of community-acquired pneumonia in the era of pneumococcal resistance: conclusions from the CDC working group 1. The current CLSI (NCCLS) categories for defining susceptibility
concentrations (i.e. penicillin G: sensitive for ≤0.06 μg/mL; intermediate for 0.1-1 μg/mL and resistant for ≥2 μg/mL) are not clinically useful for treatment of patients with pneumococcal pneumonia. Comparative studies of adults and children have reported that pneumonia due to penicillin-nonsusceptible pneumococci (most had MIC >0.1-1 μg/mL) does not influence the outcome of pneumonia treatment (175;176). At higher level of resistance (penicillin MIC 2-4 μg/mL), recent evidence suggests
that risk of mortality or suppurative complications were increased (177;178). In one study (179), the observed increase in mortality was confined to patients with pneumococcal isolates with penicillin MIC of ≥4 μg/mL.
S. pneumoniae causing pneumonia (but not otitis media and
meningitis), the following revised categorization was suggested: ≤1 μg/mL, sensitive; 2 μg/mL, intermediate; ≥4 μg/mL resistant. By modifying the breakpoints, it is hope that there will be decreased use of broad-spectrum antimicrobial therapy in favour of more narrow-spectrum therapy. Patients with pneumococcal pneumonia caused by strains with penicillin MIC ≤1 μg/mL can
be treated appropriately with optimal dosage of IV penicillin and selected other PO/IV beta-lactams. Comparative anti-pneumococcal activities of commonly used beta-lactams is shown in Table 18.
Vancomycin is not routinely indicated for treatment of CAP or for pneumonia caused by DRSP.
4. The CDC working group does not advocate the use of newer
fluoroquinolones for first line treatment of CAP. The reasons are: (a) Most
S. pneumoniae pneumonia
can be appropriately treated with a beta-lactam with good anti-pneumococcal activity at optimal dosage.
(b) Concerns that resistance among pneumococci will rapidly
emerge after widespread use of this class of antibiotics.
(c) Their activity against pneumococci with high level penicillin
resistance (MIC ≥4 μg/mL) makes it important that they be
reserved for selected patients with CAP.
Indications for use of fluoroquinolones in CAP
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(a) Adults for whom one of the first line regimen has already failed. (b) Allergic to alternative agents. (c) Documented infection due to pneumococci with high level
penicillin resistance (penicillin MIC ≥4 μg/mL).
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Regional considerations for S. pneumoniae(4;5;56;96;144;155;180-182) 1.
In Hong Kong, reduced susceptibility to penicillin and resistance to macrolides were high in both hospital (56;155) and community settings (180;181) (50-70% and >70%, respectively).
2. Erythromycin resistant isolates are also resistant to the newer
macrolides/azalides such as clarithromycin and azithromycin (183).
Globally, resistance to fluoroquinolones among the pneumococci is low (<1-2%). Hong Kong is one of the rare exceptions in which fluoroquinolone resistance (levofloxacin MIC ≥8 μg/mL) is rapidly emerging among the S. pneumoniae (56). The findings of two
recent multi-hospital studies were summarized below. Similar findings have been reported from several recent international surveillance studies (e.g. Alexander project). In local strains of S. pneumoniae, fluoroquinolone resistance is associated with
resistance to penicillin and is a result of double mutations in both targets (parC and gyrA) (156).
Percentage resistant to levofloxacin (MIC
Year Penicillin-
In view of the above, adherence to the CDC guidelines on the use of the fluoroquinolones seems appropriate. Moreover, tuberculosis is prevalent in Hong Kong and was reported to account for 10% of CAP in the elderly. Excess use of fluoroquinolones in CAP may lead to: (1) delay in diagnosis of tuberculosis; (2) increased fluororoquinolone resistance among Mycobacterium tuberculosis (184;185). Hence, this class of agents is not recommended as first line (or routine) therapy in Hong Kong for CAP. In this regard, extra-care need to be exercised in using fluoroquinolones in patients with risk factors for fluoroquinolone-resistant S. pneumoniae (186): • presence of COPD;
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Part IV: Empirical therapy
• nosocomial pneumococcal infection; • residence in old age home; and • past exposure to fluoroquinolones. Ciprofloxacin and ofloxacin should not be used to treat pneumococcal infection. Use of a suboptimal dose of fluoroquinolone should be avoided (e.g. the dose/frequency
approved by FDA for levofloxacin in CAP is 500 mg qd). Use of <500 mg and in divided doses should be avoided as these have been showed to be associated with the emergence of fluoroquinolone-resistant S. pneumoniae (156). If a respiratory
fluoroquinolone is indicated, there is evidence to suggest that the more potent ones (e.g. gemifloxacin, moxifloxacin, gatifloxacin) are less likely to lead to development of resistance.
5. Penicillin G (IV) or ampicillin (PO/IV) or amoxicillin (PO/IV) are
generally viewed as the beta-lactam drugs of choice for treating infections with penicillin-susceptible and penicillin-intermediate strains of S. pneumoniae. The following beta-lactams are not recommended because of poor intrinsic activities against S. pneumoniae: penicillin V, all first generation cephalosporins,
cefaclor, cefixime, ceftibuten, and loracarbef.
Lung infections involving strains with intermediate susceptibility to penicillin (MIC 0.1-1 μg/mL) may be treated with IV penicillin
G or oral amoxicillin (high dose).
7. Penicillins combined with beta-lactamase inhibitors (ampicillin-
sulbactam, amoxicillin-clavulanate, piperacillin-tazobactam) are active against beta-lactamase-producing organisms including H. influenzae, M. catarrhalis, and methicillin-sensitive S. aureus.
Except in-patients with mixed infection, these drugs offer no advantage over penicillin G or amoxicillin for the treatment of S. pneumoniae pneumonia, including those due to penicillin-resistant strains because beta-lactamase is not produced by S. pneumoniae. The MIC of ampicillin, amoxicillin, piperacillin for most local strains were similar to that of penicillin. However, the
MIC of ticarcillin is increased disproportionately among penicillin non-susceptible strains.
Amoxicillin capsules taken together with standard Augmentin (375 mg tablet) may be an acceptable alternative to high dose Augmentin (1 g preparation) in some clinical situations. An example of dosing for combinational use would be amoxicillin (Amoxil) 250 mg tds + Augmentin 375 mg tds. While they are expected to produce similar pharmacodynamic targets (T>MIC) (187), no specific pharmacokinetic studies have been conducted
to demonstrate their bioequivalence.
IMPACT Third Edition (Version 3.0)
Part IV: Empirical therapy
Table 18. Comparative activities of commonly used beta-lactams against Streptococcus pneumoniae with different levels of penicillin susceptibility

Spam Classification Documentation What is SPAM? "Unsolicited, unwanted email that was sent indiscriminately, directly or indirectly, by a senderhaving no current relationship with the recipient."Objective: 1. Develop an algorithm apart from Bayesian probabilities,i.e through Frequent item set Mining, Support Vector Machines (SVM).